The morbidity and mortality associated with African trypanosomiasis, Chagas disease, and leishmaniasis may exceed better-known conditions such as of HIV/AIDS, tuberculosis, or malaria. These neglected diseases affect millions of people around the world, causing thousands of deaths and affecting the ability of more people to raise cattle, and crops, or earn a living. No vaccines are available to prevent them and drug treatments have serious side effects or are not completely effective. The study of metabolic pathways in these parasites that may be essential for their survival but may not find an equivalent counterpart in their host could provide information on potential new targets that could be exploited for development of new therapeutic approaches. The goal of this application is to continue our studies of the roles of acidocalcisomes and polyphosphate in Trypanosoma brucei. Our hypothesis is that the characterization of the acidocalcisome and polyphosphate functions in trypanosomes will lead to important insights into the biology of these parasites, and ultimately novel targets for anti-parasitic intervention. We have identified a novel metabolic pathway in trypanosomes involving the synthesis of inositol pyrophosphates, and found a number of polyphosphate-binding proteins. These findings, together with the recent discoveries of the roles of polyphosphate in inflammatory reactions and as a primordial chaperone greatly enhance our chances to discover novel metabolic pathways and targets for anti- parasitic drugs. We will investigate the link between inositol pyrophosphates (InsPPs), polyphosphate (polyP) synthesis, and acidocalcisomes, the function of InsPPs, and the role of polyphosphate as a chaperone in trypanosomes.